Method of restoring the incretin effect

ABSTRACT

The present invention relates to methods of treating metabolic syndrome, Type 2 diabetes mellitus, atherogenic dyslipidemia and/or obesity. The present invention also relates to methods of restoring the incretin effect, to restoring physiologic control of glucagon levels, to restoring first-phase insulin secretion, and to restoring the physiologic glucose-dependent insulin secretion. The methods of the present invention comprise administration of a selective κ-receptor antagonist, such as guanidinylated naltrindole (GNTI), or pharmaceutically acceptable derivatives thereof to a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/862,227, filed Oct. 20, 2006.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not applicable.

INTRODUCTION

Insulin secretion is stimulated to greater extent by oral intake ofglucose than by intravenous intake of glucose. This effect, which iscalled the incretin effect, is estimated to be responsible for more thanhalf of the insulin response to glucose. The incretin effect is causedmainly by the two intestinal insulin-stimulating hormones, glucagon-likepeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP). In patients with Type 2 diabetes mellitus, and other componentsof the metabolic syndrome, such as impaired glucose tolerance,atherogenic dyslipidemia, overweight and obesity, the incretin effect iseither greatly impaired or absent.

The rapid and sizable increase in insulin release initiated by theincretin effect begins within two minutes of nutrient ingestion andcontinues for up to 15 minutes. This post-meal increase in insulin isreferred to as first phase insulin secretion. A second phase of insulinsecretion follows and is sustained until normal blood glucose levels arerestored. Clinical observations reveal that patients with metabolicsyndrome disorders such as Type 2 diabetes mellitus, impaired glucosetolerance, and obesity are characterized by progressive reductions inthe magnitude of first-phase insulin secretion, insulin resistance, andbeta-cell dysfunction, creating a new pathogenic platform shared by allcomponents of the metabolic syndrome. Beta-cell dysfunction is, in turn,characterized by its two contributing components: (1) the progressiveimpairment of insulin production, and (2) the progressive impairment ofphysiologic control of insulin release. It follows, that the metabolicdisorders should be correctable by the treatment, or restoration, of thefailing components of the underlying pathogenic platform of insulinresistance and beta-cell dysfunction.

Glucose intolerance includes a continuous range of impairments incarbohydrate metabolism. Type 2 diabetes mellitus, impaired glucosetolerance, and impaired fasting glucose, among other conditionsassociated with glucose intolerance, have been implicated as riskfactors contributing to heart disease, stroke, overweight, obesity,hypertension, and atherogentic dyslipidemia.

The pathogenesis of obesity is associated with other components of themetabolic syndrome, like atherogenic dyslipidemia, and glucoseintolerance, the magnitude of which may progress over time. Thresholdlevels for pharmacological treatment have, therefore, been reviseddownward on several occasions in order to intervene at an earlier stagein the epidemic expansion of the affected population, and thecorresponding health care expenditures. Non-insulin therapies areavailable to reduce endogenous gluconeogenesis or improve peripheralinsulin sensitivity, e.g., metformin, sulfonylureas orthiazolidinediones (TZD). However, these therapies fail to restorefirst-phase insulin release or the incretin effect. Importantly,enhanced early insulin release is associated with improved overallglucose tolerance. There is, currently, no treatment available torestore or reactivate the natural physiology of the native incretinsystem.

SUMMARY

The present invention relates to methods of treating metabolic syndrome,Type 2 diabetes mellitus, atherogenic dyslipidemia and/or obesity. Thepresent invention also relates to methods of restoring the incretineffect, to restoring physiologic control of glucagon levels, torestoring first-phase insulin secretion, and to restoring thephysiologic glucose-dependent insulin secretion.

The methods of the present invention comprise administration of aselective κ-receptor antagonist such as guanidinylated naltrindole(GNTI), or a pharmaceutically acceptable derivative thereof, to asubject in need thereof. The selective κ-receptor antagonist may beadministered daily, weekly or at any suitable time interval.Administration may be sublingually, orally, enterally, parenterally,topically or systemically. The selective K-receptor antagonist may beco-administered with an insulinotropic agent. The insulinotropic agentmay be an extended release formulation.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 illustrates the blood glucose readings of a male subject treatedwith GNTI over an extended period of time as described in Example 1.

FIG. 2 illustrates the blood glucose readings of a male subject treatedwith GNTI over a modal week as described in Example 1.

FIG. 3 illustrates the blood glucose readings of a male subject treatedwith GNTI over a modal day as described in Example 1.

DETAILED DESCRIPTION

It has surprisingly been discovered that the administration of aselective κ-receptor antagonist, such as GNTI, is useful in thetreatment of metabolic syndrome by targeting the incretin effect. Theterm “selective κ-receptor antagonist” means a κ-receptor antagonistcharacterized by its μ/κ antagonism K_(e) selectivity ratio, as definedin J. Med. Chem 43, 2759-2769 (2000), the ratio required for this methodbeing>35. Suitably, the selective κ-receptor antagonist actsperipherally. That is, it is substantially free of CNS activity.

The term “metabolic syndrome” may include, but is not limited to,atherogenic dyslipidemia, pre-diabetes, overweight/obesity, Type 2diabetes mellitus and essential hypertension. The pathogenesis ofobesity is associated with other components of the metabolic syndrome,e.g., atherogenic dyslipidemia, and glucose intolerance, the magnitudeof which may progress, from its initial stages characterized by impairedfasting glucose, followed by impaired glucose tolerance and culminatingin Type 2 diabetes mellitus. Administration of a selective κ-receptorantagonist, or a pharmaceutically acceptable derivative thereof has beenfound to restore the incretin effect, restore physiological control ofglucagon levels in response to ingested nutrition, restore first-phaseinsulin secretion, restore glucose-dependent insulin secretion, reduceweight gain and/or lower weight in a subject without co-administrationof a κ-agonist.

As will be appreciated, the methods described herein may be useful inboth research and clinical settings, suitably wherein treatment ofcertain disease states are implicated, including, but not limited to,impaired glucose tolerance, Type 2 diabetes mellitus, diminished orabsent first-phase insulin secretion, and obesity.

The administration of a selective K-receptor antagonist to a subject inneed thereof may treat metabolic syndrome. Administration of a selectiveκ-receptor antagonist may treat metabolic syndrome by restoring theincretin effect, by restoring physiologic control of glucagon levels, byrestoring the physiologic glucose dependent insulin secretion, and/or byrestoring first-phase insulin secretion. Suitably, the administration ofa selective κ-receptor antagonist may also treat overweight, atherogenicdyslipidemia obesity or Type 2 diabetes mellitus by restoring theincretin effect, by restoring physiologic control of glucagon levels, byrestoring the physiologic glucose dependent insulin secretion, and/or byrestoring first-phase insulin secretion.

The administration of a selective κ-receptor antagonist to a subject inneed thereof restores the incretin effect. In a subject having a normalresponse to oral nutrient administration, the release of theinsulinotropic hormones, GIP and GLP-1, results in an increase ininsulin secretion. This is called the “incretin effect”. As used herein,to “restore,” for example, with respect to the incretin effect, suitablyincludes enhancing, potentiating, increasing, reestablishing,re-activating, or improving the physiological state. For example, asubject having Type 2 diabetes mellitus may exhibit diminished or evenzero incretin effect, i.e., diminished or no activity of GIP or GLP-1,or diminished or no increase in insulin secretion upon nutrientadministration. Consequently, to “restore” the incretin effect suitablyincreases, though does not necessarily normalize, GIP or GLP-1 activityor insulin secretion upon nutrient administration in a subject. Thesubject is suitably a mammal, such as a human, dog, cat, primate, etc.

The administration of a selective x-receptor antagonist may restorephysiologic control of glucagon levels in a subject in need thereof. Asused herein, to “restore,” for example with respect to physiologiccontrol of glucagon levels, suitably includes, decreasing, lowering,regulating, reestablishing, or improving the physiologic state. In asubject having a ‘normal’ physiologic response to nutrientadministration, physiologic control of glucagon primarily responds toblood glucose levels, i.e., as blood glucose levels decline, glucagon isreleased from the a cells of the islets of Langerhans in the pancreas,and act on the liver to induce gluconeogenesis, i.e., endogenous glucoseproduction, and/or glycogenolysis. Conversely, glucagon releasedecreases in response to increasing blood glucose levels. Additionally,glucagon levels decrease in response to release of insulin by pancreaticβ-cells. Consequently, in a subject having abnormal insulin productionor release in response to increasing blood glucose levels, glucagonrelease may remain abnormally high and result in hyperglucagonemia whichfurther exacerbates conditions such as Type 2 diabetes mellitus andimpaired glucose tolerance.

Normal insulin secretion from the pancreatic β cells is biphasic. Theinitial release of insulin that acts on the pancreatic α cells todecrease glucagon is referred to as the first-phase of insulinsecretion. First-phase insulin secretion is characterized by a rapid andsizable increase in insulin, beginning within two minutes of nutrientingestion, and continuing for 10-15 minutes. For example, in Examples 3and 4, first-phase insulin secretion can be seen at the 5-minute timepoint coupled with a corresponding drop in glucagon levels. Two minuteslater, blood glucose levels show an initial decrease. The second phaseof insulin secretion follows and insulin secretion peaks approximately1-2 hours following nutrient ingestion. Insulin secretion continuesuntil normal blood glucose levels are restored. Often, in subjectshaving impaired glucose tolerance, first-phase insulin secretion isreduced and it is believed that the reduction in first-phase insulinsecretion may be a preliminary sign in the progression of Type 2diabetes mellitus.

The administration of a selective κ-receptor antagonist restoresfirst-phase insulin secretion in a subject in need thereof. Theadministration of a selective κ-receptor antagonist may restore thephysiologic glucose dependent insulin secretion in a subject in needthereof, and a selective κ-receptor antagonist may restore thephysiologic control of glucagon release.

The methods described herein restore the incretin effect, first-phaseinsulin secretion and/or physiologic insulin secretion throughadministration a selective κ-receptor antagonist. Suitably, the presentinvention may also provide a method of treating Type 2 diabetesmellitus, atherogenic dyslipidemia, obesity/overweight or metabolicsyndrome through administration of a selective κ-receptor antagonist.The administration of an effective amount of a selective κ-receptorantagonist may reduce weight gain or lower weight in a subject in needthereof.

Suitably, an insulinogenic agent may be used in combination with aselective κ-receptor antagonist. An “insulinogenic agent” stimulates,participates in the stimulation of, or potentiates the biosynthesis ofinsulin by the pancreatic β-cells. Examples of insulinogenic agentsinclude sulfonylureas, repaglinide, nateglinide, mitiginide andBTS-67-582. Suitably, the insulinogenic agent is provided in an extendedrelease composition, i.e., the insulinogenic agent is formulated suchthat it is released over a period of time. An extended releaseinsulinogenic agent acts to potentiate the synthesis of insulin.

Pharmacologically equivalent derivatives of a selective κ-receptorantagonist include any pharmaceutically acceptable salts, hydrates,esters, ethers, amides, or any other derivative which is notbiologically or otherwise undesirable and induces the desiredpharmacological and/or physiological effect.

The selective κ-receptor antagonist and the insulinogenic agent(together referred to as “active agent”) are suitably administered in apharmaceutical composition, which include the active agent(s) and one ormore pharmaceutically acceptable excipients such as stabilizers,anti-oxidants, binders, coloring agents, emulsifiers. The pharmaceuticalcomposition may be administered as a solution, an emulsion, asuspension, a dispersion, a transdermal patch, a pill, a tablet or acapsule. One of ordinary skill in the art would be able to formulate thepharmaceutical composition using the appropriate solid, liquid or gelcarriers. The selective κ-receptor antagonist and the insulinogenicagent may be formulated separately or together.

Various methods for administration of the active agent(s) may beemployed. For example, the active agent(s) may be given sublingually,orally, enterally, parenterally, topically, systemically or may beinjected intravascularly, subcutaneously, peritoneally, and so forth.The active agent(s) may be administered weekly, semi-weekly, daily, ormultiple times a day, such as twice a day or three times a day. Theselective κ-receptor antagonist and the insulinogenic agent may beadministered concurrently. Alternatively, the selective κ-receptorantagonist may be administered before or after administration of theinsulinogenic agent.

The dosage of a selective κ-receptor antagonist will vary widely,depending upon the frequency of administration, the manner ofadministration, and the clearance of a selective κ-receptor antagonistfrom the subject. It will be appreciated that the specific dosageadministered in any given case will be adjusted in accordance with thecondition of the subject and other relevant medical factors that maymodify the activity of the selective κ-receptor antagonist. For example,the specific dose for a particular patient depends on age, body weight,general state of health, diet, the timing and mode of administration,the rate of excretion and medicaments used in combination. For example,a suitable weekly dose of a selective κ-receptor antagonist may be lessthan about 300 ng per kg of body weight. Alternatively the weekly doseof a selective κ-receptor antagonist may be less than about 200 ng perkg of body weight, less than about 150 ng per kg of body weight or lessthan about 100 ng per kg of body weight. The initial dose may be larger,followed by smaller maintenance doses. The dose may be administered asinfrequently as weekly or biweekly, or fractionated into smaller dosesand administered daily, semi-weekly, etc. to maintain an effectivedosage level. A suitable daily dosage of a selective κ-receptorantagonist is less than about 80 ng per kg of body weight. Alternativelythe daily dosage of a selective κ-receptor antagonist may be less thanabout 50 ng per kg of body weight, less than about 25 ng per kg of bodyweight, or less than about 20 ng per kg of body weight.

The dosage of the insulinogenic agent will vary depending on thecondition of the subject or other relevant medical factors that modifythe activity of the insulinogenic agent or the response of the subject.For example, the specific dose for a particular patient depends on theseverity of glucose intolerance, age, body weight, general state ofhealth, diet, the timing and mode of administration, the rate ofexcretion, and medicaments used in combination. The initial dose may belarger, followed by smaller maintenance doses. The dose may beformulated for extended release, and administered as infrequently asweekly or biweekly, or fractionated into smaller doses and administereddaily, semi-weekly, weekly, etc. to maintain an effective dosage level.One of ordinary skill in the art would be able to determine theappropriate dose of the insulinogenic agent.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. It should also be noted that the term “or”is generally employed in its sense including “and/or” unless the contentclearly dictates otherwise. All publications, patents and patentapplications referenced in this specification are indicative of thelevel of ordinary skill in the art to which this invention pertains. Allpublications, patents and patent application's are herein expresslyincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference. In case of conflict between the presentdisclosure and the incorporated patents, publications and references,the present disclosure should control.

It also is specifically understood that any numerical range recitedherein includes all values from the lower value to the upper value,i.e., all possible combinations of numerical values between the lowestvalue and the highest value enumerated are to be considered to beexpressly stated in this application. For example, if a concentrationrange is stated as 1% to 50%, it is intended that values such as 2% to40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in thisspecification. For further example, if a dosage is stated as less thanabout 250 ng/kg of body weight, it is intended that values such as 50 to200 ng per kg of body weight, and 100 to 200 ng per kg of body weightare expressly enumerated in this specification. These are only examplesof what is specifically intended.

The present invention is further explained by the following examples,which should not be construed by way of limiting the scope of thepresent invention.

EXAMPLE 1 Evaluation of Blood Glucose in a Human

The daily blood glucose profile of a male subject with early stage,[non-insulin dependent] Type 2 diabetes was monitored during extendedperiods of administration of guanidinylated naltrindole (GNTI). Asummary of the blood glucose reading is shown in Table 1.

TABLE 1 Summary Average, mg/dL 92 Highest Blood Glucose, mg/dL 127Lowest Blood Glucose, mg/dL 61 Standard Deviation, mg/dL 14 Number ofGlucose Readings 227 Days Covered 15 Number of Days Without Tests 0Average Readings Per Day 15.1 Deleted Glucose Readings 0 ControlReadings 13 Deleted Control Readings 0 Average of Recorded Daily InsulinShots with All Days Covered: 0.0 with Days with Insulin Records: 0.0

A weekly dose of about 70 ng/kg was administered. The subject's bloodglucose (BG) levels were measured in mg/dL at time intervals as shown inTable 2.

TABLE 2 Early Overall AM Morning Midday Evening Night Time Range 00:0005:00 11:00 15:00 19:00 04:59 10:59 14:59 18:59 23:59 Average, mg/dL 9279 90 92 91 95 Std. Dev. mg/dL 14  3 12 14 13 15 Number of 227  4 65 5644 58 Readings Very Highs, >300 Highs, 156-300 In Target, 65-155 98%100% 97% 98% 100% 97% Lows, 51-64  2%  3%  2%  3% Very Lows, <51

FIGS. 1-3 illustrate the blood glucose readings over an extended periodof time, a modal week and a modal day. The target blood glucose rangewas 65-155 mg/dL. Table 3 illustrates that 98% of the readings werewithin the target range. The other 2% of the readings fell below thetarget range and fell between 51-64 mg/dL. Note that none of thesereadings were in the hypoglycemic range.

TABLE 3 Reading/Range Glucose Ranges, mg/dL Number Percent Very High(301-601) 0 0% High (156-300) 0 0% Target (65-155) 222 98% Low (51-64) 52% Very Low (0-50) 0 0%

FIGS. 1-3 illustrate the subject's blood glucose readings over anextended period of time, a modal week, and a modal day. Accordingly, 227blood glucose readings were taken, averaging 92 mg/dL over a 15 dayperiod. 98% of all readings were between 65 and 127 mg/dL, and 2%between 61 and 65, representing a very narrow overall spread. These dataexemplify glucose dependent insulin secretion, one of thecharacteristics of GNTI mediated incretin targeted treatment of Type 2diabetes mellitus subjects.

Table 4 illustrates the blood glucose statistics by day of week. Thesedata illustrate that once weekly administration of GNTI aided inmaintaining blood glucose levels within the target range.

TABLE 4 Blood Glucose Statistics by Day of Week, mg/dL Week- Week- daysends Mon Tue Wed Thur Fri Sat Sun Average, mg/dL 92 92 92 87 88 94 96 9292 Std. Dev, mg/dL 15 12 11 17 15 14 15 10 13 Number of 148 79 30 23 2836 31 32 47 Readings Very Highs, >300 Highs, 156-300 In Target, 65-15597 100 100 87 93 100 100 100 100 (as %) Lows, 51-64 3 13 7 (as %) VeryLows, <51

The weight of the male subject with early stage Type 2 diabetes mellituswas also monitored during extended periods of administration on GNTI,decreasing from a baseline body mass index (BMI) of 25 to an average BMIof 22.8, corresponding to a reduction by about 9%.

EXAMPLE 2 Evaluation of Blood Glucose in Rhesus Monkeys

A cohort of rhesus monkeys having progressively increasing degrees ofimpaired glucose tolerance were monitored following an oral dose of GNTIof 86 ng/kg of body weight. Baseline readings of blood glucose (BG),high density lipoprotein C (HDL-C) and triglycerides (TG) were taken onDay 0. Table 5 shows the baseline readings on Day 0 and the results ofthe second reading on Day 8 of BG, HDL-C and TG.

TABLE 5 Oral Dose BG HDL-C TG Animal Sequence GNTI mg/dL mg/dL mg/dLr89163 Baseline 65 64  59 Day 0 86 ng/kg Day 8 63 84  60 Change   (−3%)(+)31% (—) r98068 Baseline 71 81 <45 Day 0 86 ng/kg Day 8 51 85 <45Change (−)29%  (+)5% (—) r96027 Baseline 74 44 112 Day 0 86 ng/kg Day 853 46  89 Change (−)28% (+)10% (−)10% r00072 Baseline 80 48 <45 Day 0 86ng/kg Day 8 67   6.1 <45 Change (−)16% (+)27% (—) r01078 Baseline 81 51<45 Day 0 86 ng/kg Day 8 56 63 <45 Change (−)30% (+)24% (—)

The effect of GNTI was most readily seen in the change of blood glucoseand blood lipid levels. Subject r89163 had a baseline blood glucoselevel of 65, i.e., a “normal” fasting blood glucose level for a rhesusmonkey. The other 4 subjects of the cohort, i.e., r98060, r96027,r00072, r01078, had baseline blood glucose levels ranging from 71-81 andwere considered to have impaired glucose tolerance. On day 8, thesubjects having impaired glucose tolerance showed a decrease in bloodglucose ranging from 16%-30% with an average of 26%. Comparatively, theglucose “normal” subject (r89163), receiving the same GNTI dose,exhibited a decrease in blood glucose levels of 3% only, and in aglucose dependent manner, a characteristic feature of physiologicalincretin action. The lipid “normal” subject (r98068) exhibited anincrease in HDL-C lipid levels of only 5%, where the four dyslipidemicsubjects (r89163, r96027, r00072, r01078) exhibited an HDL-C increase inthe range of 10-31%, with an average of 23%.

EXAMPLE 3 Development of a Meal Tolerance Test (MTT)

To test for the effect of physiological first phase insulin secretion, ameal tolerance test (MTT) was developed. The meal tolerance testinvolved oral administration of meal based nutrients within suitableratios of carbohydrates, proteins and fats. The ratios used for thegiven example were 70% carbohydrates, 8% protein and 22% fats. Prior toadministration of a MTT to subject r89163, baseline blood glucose,insulin and glucagon readings were taken as seen in Table 6. FollowingMTT administration, the same readings were taken at time points of 3-9minutes to test for first-phase insulin secretion and the subsequentreduction in blood glucose. It was determined that a first-phase insulinsecretion dependent slight increase in insulin concentration appeared,typically, at 5 minutes post MTT administration, followed by acorresponding blood glucose decrease at 7 minutes. A slight decrease inglucagon levels was also coupled with first-phase insulin secretion at 5minutes. The MTT serves as a corollary to the intravenous glucosetolerance test (IVGTT) and better measures first-phase insulin secretionbecause oral administration of nutrients has a more direct effect on theincretin effect.

TABLE 6 Glucagon Test Points TestMealCal BG Insulin GIP GLP-1 GlucagonChange Animal Min Drug C/P/F (%) Mg/dL microU/mL Pg/mL Pmol/L Pg/mLT0-T60/120 R89163 None 70/8/22 T-0 69.8 24.43 506.96 Test MealAdministration T-3 73.3 15.17 506.86 T-4 73.3 28.85 517.64 TP5/Ins. 76.734.63 480.54 T-6 76.1 32.8 456.43 TP7/BG 74.3 32.02 430.75 T-8 75.524.81 448.98 T-9 75.6 24.73 481.24

EXAMPLE 4 Application of the Meal Tolerance Test

Table 7 illustrates administration of the MTT to two rhesus monkeyscategorized as metabolically “normal” based on “normal” fasting bloodglucose values. The monkeys were given a diet of 55-60% carbohydrates,15-25% protein, and 15-30% fat. Readings of blood glucose, insulin, andglucagon were taken at time points 0, 5, 7, 60 and 120 minutes.Additionally, at the same time points, the incretin hormones, GIP andGLP-1 were measured to more directly measure the incretin effect. Insubject r98038, a significant increase in insulin and concurrent drop inglucagon were seen at time point 5, as would be expected. One hour afterMTT administration very significant increases in insulin, GIP and GLP-1were seen in subject r98038, again coupled with consecutive decreases inglucagon. Comparison of blood glucose levels at time points 0 and 120minutes illustrates that normal metabolic functioning has returned thesubject's blood glucose levels to normal within 120 minutes of MTTadministration.

By contrast, subject r91081 appears from its baseline blood glucoselevel to be a “normal” metabolic subject. However, the characteristicfirst-phase insulin secretion at time point 5 following MTTadministration is lacking as is the time point 7 blood glucose decrease.Further analysis showed that at 120 minutes following MTT administrationthe blood glucose and glucagon values were markedly higher than thebaseline readings. These results contradict the results for “normal”subject r98038, and strongly indicate impaired metabolic control whichwas not discernable from the fasting blood glucose value.

TABLE 7 Glucagon Test Points TestMealCal BG Insulin GIP GLP-1 GlucagonChange Animal Min Drug C/P/F (%) Mg/dL microU/mL Pg/mL pmol/L Pg/mLT0-T60/120 r98038 None 74/6/20 TP 0 min 58.15 15.68 <8 12.8 180.79 TP 5min 70 25.52 <8 13.6 145.5 TP 7 min 71.15 17.16 <8 11.3 243.26 TP 60 min53.7 108.56 640 26.6 182.7 (+) 1% TP120 min 56.3 43.97 560 34.9 138.22(−) 23% r91081 None 70/8/22 TP 0 min 56.15 24.71 175 196 99.8 TP 5 min63.05 32.44 160 178 95.4 TP 7 min 64.5 59.48 150 146 90.51 TP 60 min63.85 111.1 950 141 114.49 (+) 14.7% TP120 min 78.15 202.29 950 124145.32 (+) 45.6%

EXAMPLE 5

Table 8 illustrates the effect of GNTI on physiologic control ofglucagon levels. Baseline readings were taken on Day 1 of blood glucose,insulin, glucagon, GIP, and GLP-1 in metabolically impaired rhesusmonkeys as determined through administration of the MTT. Cumulativein-situ doses of 45 ng/kg and 95 ng/kg were active on day 5 and day 7,respectively, during administration of the MTT. Readings of bloodglucose, insulin, glucagon, GIP, and GLP-1 were taken at time points 0,60 minutes and 120 minutes. As Table 8 illustrates, both dosagesresulted in a marked decrease in glucagon at both time points 60 and 120in all subjects tested. Comparison to untreated subject r91081 in Table7 further demonstrates the marked decrease in glucagon.

TABLE 8 Test Points Glucagon 0/60/120 GNTI TestMealCal BG Insulin GIPGLP-1 Glucagon Change Animal Minutes ng/kg C/P/F (%) mg/dL microU/mLpg/mL pmol/L pg/mL T0-T60/120 r96022 Day 1 Baseline No Drug 64 16 25 13394 Day 5 TP 0 min 45 ng/kg 73/9/18 51 14 8 11 411 TP 60 min 64 122 65031 267 −35% TP120 min 67 200 n/a 31 261 −36% Day 7 TP 0 min 95 ng/kg74/7/19 56 14 30 28 472 TP 60 min 70 100 675 35 240 −49% TP120 min 63 54675 n/a 271 −43% rh2251 Day 1 Baseline No Drug 76 11 140 13 377 Day 5 TP0 min 45 ng/kg 73/9/18 83 57 50 34 411 TP 60 min 98 396 640 83 366 −11%TP120 min 78 249 760 82 249 −39% Day 7 TP 0 min 95 ng/kg 75/6/19 82 7125 60 487 TP 60 min 106 401 675 n/a 351 −28% TP120 min 95 307 775 223267 −45% rh2258 Day 1 Baseline No Drug 74 15 n/a 10 316 Day 5 TP 0 min45 ng/kg 74/8/18 69 23 n/a 19 302 TP 60 min 70 145 320 49 172 −43% TP120min 76 137 775 79 122 −60% Day 7 TP 0 min 95 ng/kg 74/7/19 73 30 20 67293 TP 60 min 69 54 75 60 107 −63% TP120 min 86 71 240 77 108 −63%

While the present invention has now been described and exemplified withsome specificity, those skilled in the art will appreciate the variousmodifications, including variations, additions, and omissions that maybe made in what has been described. Accordingly, it is intended thatthese modifications also be encompassed by the present invention andthat the scope.

1-37. (canceled)
 38. A method of treating type 2 diabetes mellituscomprising administering to a subject a therapeutically effective amountof a selective .kappa.-receptor antagonist, or a pharmaceuticallyacceptable derivative thereof.
 39. The method of claim 38, wherein theselective .kappa.-receptor antagonist is GNTI.
 40. The method of claim38, wherein the selective .kappa.-receptor antagonist is administeredweekly or daily.
 41. The method of claim 40, wherein the selective.kappa.-receptor antagonist is administered weekly in an amount fromabout 30 ng to about 300 ng per kg of body weight weekly.
 42. The methodof claim 40, wherein the selective .kappa.-receptor antagonist isadministered daily in an amount from about 8 ng to about 80 ng per kg ofbody weight daily.
 43. The method of claim 38, wherein the selective.kappa.-receptor antagonist is administered sublingually, orally,enterally, parenterally, topically, systemically or injectedintravascularly, subcutaneously, peritoneally.
 44. The method of claim38, further comprising co-administration of an effective amount of aninsulinogenic agent.
 45. The method of claim 44, wherein theinsulinogenic agent is an extended release composition.
 46. The methodof claim 38, wherein a .mu.-agonist is not co-administered. 47-77.(canceled)